Methods for treating pain



United States Patent 3,317,388 METHODS FOR TREATING PAIN Bola Vithal Shetty and Liborio A. Campanella, Rochester, N.Y., and Edwin E. Hays, Northridge, Calif., assignors to Wallace & Tiernan lno, Belleville, N.J., a corporation of Delaware No Drawing. Filed Nov. 20, 1964, Ser. No. 412,840 4 Claims. (Cl. 167-65) The invention relates to the treatment of pain.

We have discovered that certain quinaz-olinone compounds are potent analgesics, useful in alleviating pain in animals, including rats, dogs, rabbits, chickens, cows, and humans. v

The free base and the pharmaceutically acceptable acid addition salts are suitable. The free base is represented by the following general formula:

The free base of the compounds comprising this invention may be represented by the following general formula:

where R and R may be hydrogen, lower alkyl, or trifluoromethyl.

The lower alkyl of R may suitably be in the ortho, meta or para position.

Some examples of suitable acid addition salts of the above free bases with inorganic and organic acids are the hydrochloride, hydrobromide, hydroiodate, sulfate, phosphate, maleate, acetate, citrate, succinate, benzoate, glycolate, resinates of sulfonic and carboxylic acids, and others. These can be prepared by methods hereinafter described or well known to the art.

METHOD OF TESTING AND RESULTS General procedure Manor Farm rats of either sex and weighing from 83 to 125 grams were used in this study. The rats were separated int-o treated groups of five each per dosage level of compound administered. A non-treated group of five rats were simultaneously utilized with each test. All of the animals were fasted for 16 hours prior to use.

On the day of the test two threshold pressure values obtained one hour apart (recorded in mm. Hg) were recorded from both hind paws of each rat by a modified method originally described by Randall and Selitto (Arch. Int. Pharm-acodyn., 111: 409, 1957). The instrument utilized in these experiments was activated by compressed nitrogen which was regulated by two foot operated electrically controlled pneumatic air valves. One valve controlled the compressed air entering a system which terminated in an inverted ml. syringe. A blunt metal point was affixed to the barrel of the syringe. The syringe was clamped in a perpendicular plane to a heavy ring stand in such a manner that when air entered the system the barrel was driven toward the table surface. The rats foot was held manually in a specially constructed metal trough directly under the syringe barrel so that the metal point would impinge upon the plantar surface of the foot. The pressure in the system was recorded by an anemometer interposed into the system with a T tube. The end-point used was vocalization and/ or struggle and biting by the animal at the peg impinging upon the foot. The air flow into the system was maintained constant at 20 mm. Hg per second. When the end-point was reached the foot pedal was released which automatically stopped inflow air into the system and held the pressure constant at end-point. This enabled the operator to read the rum.

3 ,317,388 Patented May 2, 1967 l-Ig pressure without error. A second foot pedal activatmg an electrically operated pneumatic valve released air pressure after the reading had been made.

After the two initial control valves had been obtained for each rat, the right hind paw of each animal was sensitized or inflamed by a subcutaneous injection into the mid-plantar surface of 0.1 ml. of a 20 percent suspension of brewers yeast in a physiological saline solution. Control threshold pressure values were again obtained on both the inflamed and non-inflamed hind paw of each animal at one and two hours after the yeast injection. The value obtained at two hours was used as the predrug control value.

Each compound tested was administered orally at dosage levels of 5, 10 and 20 mg./kg. to groups of five rats per dosage level. A control group of five rats was ad ministered the vehicle only.

The compounds were suspended in an aqueous dispersion of 4 percent cleargel in such a manner that volumes administered to each rat could be maintained constant at 1 ml./ 100 grams of body weight.

All analgesic trials were blind studies. Not only did the operator not know which group of animals had received the test or control substances, but he also did not know the dosage levels administered to a given group. Furthermore, a helper handed animals to the operator in random fashion so that no entire group at any dosage level could be evaluated in a consecutive manner. An

RESULTS Compound 2 (n propyl)-3-(o-tolyl)-6-amino-4(3H)- quinazolinone dihydrochloride monohydrate demonstrated a significant analgesic response at all dosages employed. Peak analgesic effect with this compound occurred at 60 minutes after administration at the 5 and 10 rug/kg. dosage levels. At the 20 mg./kg. dosage level peak activity occurred at minutes after administration. Analgesia was still present at all dosage levels at the five-hour determination. Tests were not carried beyond the fivehour reading.

Threshold values for the noninflamed foot of the rats used for 2-(n-propyl)-3-(o-tolyl)-6-amino-4(3H)-quinazolinone dihydrochloride monohydrate were also increased. Even though the standard deviation of the values obtained from the control rats were great, the values obtained from the rats administered 2-(n-propyl)- 3 o-tolyl) -6-amino-4( 3 -quinazolinone dihydrochloride monohydrate were still significant at the percent level of confidence (greater than two standard deviations from the mean of the control group). These results would indicate that the analgesic activity of 2-(n-propyl)- 3-(o-tolyl)-6-amino-4(3H) quinazolinone dihydrochloride monohydrate was not due to an anti-inflammatory mechanism.

In comparison to dose response curves previously obtained with aspirin in the identical test procedure, compound 2-(n-propyl)-3-(o-tolyl-6-amino 4(3H) quinazolinone dihydrochloride monohydrate is 40 times as potent and of similar duration.

Compound 2-methyl-3-(o-tolyl)-6-amino-4(SI-D-quinazolinone did not produce an analgesic effect at dosage below 20 rug/kg. However, at 20 mg./kg., highly sig-' nificant values were obtained. Analgesic activity ap- 3 peared to peak at one hour after administration and continue for at least three hours.

Compound 3-(o-trifluoromethyl phenyl) 6 amino-4- (3H)-quinazolinone produced a very brief analgesic response at 20 mg./kg. which was significant at the halfhour and one-hour periods of examination, but not there after.

Compound 2-rnethyl-3-(p-amino-o-tolyl)-4(3H) quinazolinone produced a significant analgesic response which was slow in onset and which did not reach peak activity until four hours after administration.

PHARMACODYNAMICS Slight ataxia, sedation, fiaccidity and sluggish righting reflexes were observed from the above compounds for periods of 3090 minutes, but after three to five hours all groups of animals appeared normal with the exception that slight sedation was still detectable at the upper dose level of 20 mg./kg.

Compounds of this invention may be administered alone but are generally administered with a pharmaceutical carrier. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, clay, or the like, or in the form of elixir or oral suspension. This is true of the resinates as well as the free base and common salts. However, for parenteral and intramuscular administration the free base and common salts should be used.

The physician and veterinarian will determine the dosage which will be most suitable for a particular application; however, it has been found that doses between 10 and 400 milligrams for human patients are effective for producing satisfactory analgesia. For all animals the range may be expressed at .05 mg./kg. to 50 mg./kg. per dose. These amounts are on the basis of the free base.

The following examples are illustrative of the method of preparing the compositions of this invention:

Example I .-2-methyl-3-( o-tolyl -6-amin0-4 (3H quinazolinone A mixture of 100.0 gm. (0.44 mole) of S-nitro-Z-acetamido benzoic acid which was obtained by the oxidation of 2-rnethyl-4-nitro acetanilide, 54.0 gm. (0.5 mole) of o-toluidine and 3000 ml. of toluene was placed in a -liter, three-necked round-bottomed flask provided with a condenser protected from moisture, a stirrer and a dropping funnel. With vigorous stirring, a solution of 27.9 gm. (0.2 mole) of phosphorous trichloride and 300 ml. of toluene was added drop-wise during two hours. It was refluxed for 2 hours, cooled and neutralized with 10 percent sodium carbonate solution. The toluene layer Was separated and the aqueous layer was extracted with 100 ml. of toluene. The combined extracts were subjected to steam-distillation. The resulting solid, 2-rnethyl- 3-(o-tolyl)-6-nitro-4(3H)-quinazolinone, was removed by filtration, dried and recrystallized from methanol. The yield was 100.0 gms. The melting point was l75177 C.

Fifteen grams of the above 6-nitro derivative was reduced to the 6-amino compound using 220 ml. of absolute methanol as a solvent and 3.0 gm. of 5 percent palladium on charcoal as catalyst. After the hydrogenation was complete, the catalyst was removed by filtration and the solvent was removed in vacuo. The solid product was recrystallized from absolute methanol.

Analysis.--Calculated for C H N O: C, 72.35; H, 5. 65; N, 15.93. Found: C, 72.41; H, 5.70; N, 15.85.

chloric acid to form a hydrochloride salt. This was obtained in solid form by removal of the water by means of vacuum distillation and then purified by crystallization from absolute methanol.

-CHa I 1 1 NHCOCH2CH2CH3 -o 0 OH m arra i N STEP I Thirty grams (0.2 mole) of 2-methyl-4-nitro aniline and 40 cc. (0.25 mole) of n-butyric anhydride were mixed, refluxed for five minutes, cooled to below 50 C. and poured slowly with stirring, into 500 cc. of ether while cooling in an ice bath. The resulting solid was filtered off, air-dried, dissolved by heating with 400 cc. of methyl ethyl ketone, digested for fifteen minutes with 20.0 gms. of charcoal, filtered through filter-eel, concentrated to about 50 cc. and poured into 2 l. of petroleum ether. The solid product, N-butyryl-Z-methyl-4-nitro aniline, was removed by filtration and air-dried, wt.=28.0 gms. From the filtrate, 6.0 gms. of the product was recovered. Total wt.=34.0 gms. (78%), M.P. =125.512 6.5 C.

STEP II Twenty-five grams (0.112 mole) of N-butyryl-Z-methyl-4-m'tro aniline, 50.0 gins. (0.2 mole) of magnesium sulfate heptahydrate and 1 l. of water Were placed in a 3 1., 3-necked, round-bottomed flask equipped with a stirrer, a condenser and a thermometer. The reaction mixture was heated to 75-80 C. with stirring and 100.0 gms. (0.6 3 mole) of potassium permanganate was added portionwise during a period of 5 hours. The stirring and heating at 80 C. was continued for an additional one hour, the reaction mixture was cooled to below 50 C., filtered and the insoluble residue was washed with 200 cc. of water. The combined filtrate was acidified with sulfur dioxide. The resulting solid product, N-butyryl-S-nitro anthranilic acid, was removed by filtration and airdried, wt.=16.0 g. (57% M. P.=175176.5 C.

STEP III Twenty-three grams (0.091 mole) of N-butyryl-S-nitro anthranilic acid, 11.0 gms. (0.1 mole) of o-toluidine and 400 cc. of toluene were placed in a 2 1., S-necked round-bottomed flask equipped with a stirrer, a condenser and a dropping funnel. With vigorous stirring, 14.5 gms. (0.1 mole) of phosphorous trichloride was added dropwise during a period of one hour. The reaction mixture was refluxed for 3 hours, cooled to below 30 C. and neutralized with 10% sodium carbonate solution. The toluene layer was separated and the aqeous layer was extracted with cc. of toluene. The combined toluene solutionwas subjected to steam-distillation. The resulting mixture was cooled and the solid, Q-(n-propyl)-3-(o-tolyl)- 6-nitro-4(3H)-quinazolinone was filtered otf, dried and recrystallized twice from 300 cc. each of absolute methanol, wt.'=18.'0 gms. (65% M.P.=119-121 C.

'STEP IV 200 cc. each of .absolute methanol and 50 cc. of an-v hydrous ether and dried in vacuo, wt. =6.7 gm. (40%), M.P.=177-179 C.

Following the same or analogous procedures as set forth in the above examples, the other quinazolinone compounds disclosed and claimed herein can be prepared.

Example I V.2-meihyl-3- o-tolyl -6-amin0-4 (3H -quinazolinone ionically bound to a sulfonic acid cation exchange resin To 370 gms. of moist Amberlite IR-1 20 resin (225 gms. of dry resin) suspended in distilled water was added an amount of -2-methyl-3-(o-tolyl)-6-amino-4(3H)-quinazolinone sufiicient to yield a product containing approximately 40 percent 2-methyl-3-(o-tolyl)-6-amino-4(3H)- quinazolinone. The mixture Was stirred for two hours, filtered, and dried for fifteen hours at 60 C. The drugresin complex was found to contain 41 percent 2-methyl- 3-(o-tolyl)-6-amino-4(3H)-quinazolinone.

Following the same or analogous procedure as set forth in Example IV, the other qinazolinone compounds disclosed herein can be adsorbed upon and ionically bound with sulfonic acid cation exchange resins or other cation exchange resins, to produce the compositions of the present invention. Such drug-resin complexes may be administered to patients as prepared, or mixed with the usually acceptable excipients. Aqueous suspensions of the resin adsorption compositions can be made and are particularly adapted to be mixed with syrups, such as those made with glucose, sucrose or glycerin, and thus administered to patients in liquid form.

While certain embodiments of the invention have been described, many modifications thereof may be made without departure from the spirit of the invention; and it is not wished to be limited to the detailed examples, formulas and proportions of ingredients herein set forth. It is desired to be limited only as required by the appended claims.

We claim:

1. The method of alleviating pain in a warm-blooded animal suffering from pain which comprises administering to said animal an effective amount of a compound selected from the group consisting of compounds of the formula:

animal suffering from pain which comprises administering to said animal an effective amount of 2-(n-propyl)-3- o-tolyl) -6-amino-4( 3H) -qu.inazolinone dihydrochloride monohydrate.

4. The method of alleviating pain in a warm-blooded animal suffering from pain which comprises administering to said animal an effective amount of 3-(0-trifluoromethyl phenyl) -6-amino-4 3H) -quinazolinone.

References Cited by the Examiner UNITED STATES PATENTS 3,060,090 /1962 Becker 1'67-6S FOREIGN PATENTS 919,139 1/ 1963 Great Britain.

ALBERT T. MEYERS, Primary Examiner. S. I. FRIEDMAN, Assistant Examiner. 

1. THE METHOD OF ALLEVIATING PAIN IN A WARM-BLOODED ANIMAL SUFFERING FROM PAIN WHICH COMPRISES ADMINISTERING TO SAID ANIMAL AN EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA: 